自身免疫病患者T细胞表面共刺激信号分子表达异常与免疫功能紊乱的研究
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摘要
目的 分析非器官特异性自身免疫性疾病系统性红斑狼疮(SLE)和类风湿性关节炎(RA)患者外周血T淋巴细胞及其亚群、活化或抑制T淋巴细胞的CD28、CD152(CTLA-4)共刺激分子对、效应T淋巴细胞活化共刺激分子ICOS、参与T、B淋巴细胞活化的CD154、CD30分子、参与细胞稳态调节的细胞表面凋亡受体CD95分子和参与细胞免疫调节效应的细胞因子IL-10和IFN-γ的表达,探讨人类SLE和RA疾病中T淋巴细胞免疫紊乱状态,及这些信号分子在参与人类自身免疫性疾病免疫调节过程中的作用和路径,以期为免疫干预治疗寻找理想的靶位点奠定基础。
方法 分析80例SLE患者(包括非狼疮性肾炎患者54例——其中非活动期患者24例、活动期患者30例,狼疮性肾炎患者26例),83例RA患者,40例健康志愿者外周血中T淋巴细胞免疫紊乱状态,采用流式细胞技术检测SLE、RA疾病组和健康对照组外周血或单个核细胞悬液中T淋巴细胞亚群表面共刺激分子CD28、CD152(CTLA-4)、ICOS(可诱导共刺激分子)、CD154(CD40L)、CD30分子和凋亡受体CD95(Fas)分子表达,酶联免疫吸附分析(ELISA)技术检测SLE患者组和健康对照组
Objective To analyse the expression of peripheral blood T lymphocyte subsets and costimulators on them CD28, ICOS, CD154 and CD30 which can activate and proliferate T cells and B cells, as well as CD152 (CTLA-4),CD95 which both play a negative role in T cells activation, proliferation——and plasma levels of cytokines EL-10 and IFN- γ in patients with Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA) to discuss the disturbance of T lymphocytes' and the costimulators' functions and pathways in human SLE and RA, further to lay the groundwork for finding better targets of biochemical therapy to patients with SLE and RA. Methods Analyse samples of 80 patients with SLE (54 patients with non-lupus nephritis, including 24 inactive and 30 active patients, and 26 patients with lupus nephritis), 83 patients with RA, and 40 healthy volunteers to learn the disturbances of peripheral blood T lymphocytes. Apply flow cytometry to determine the expressions of costimulators—CD28, CD152(CTLA-4), ICOS, CD154, CD30 and CD95 on T lymphocyte subsets—in patients with SLE or RA and healthy control, and emzyme-linked immunosorbent assay (ELISA)
to detect plasma levels of IL-10 and IFN- Y in patients with SLE and healthy control. All data are analysed by SPSS 11.0 statistics software and analysed by one-way ANOVA, Kruskal-Wallis Test or /-test, further comparing between groups by Dunnett T3 or Tamhane's T2 or Nemenyi Test. Results ? T lymphocyte subsets expression: Difference of CD3+T cell percentage between patients with SLE^ RA and healthy control is not significant (P>0.05). Compared with healthy control, in patients with SLE CD8+T cell percentage is increasing strikingly (PO.05); however, in RA CD4+T cell percentage and CD4/CD8ratio are both increasing significantly (PO.05). In different states of SLE, only patients with lupus nephritis have higher CD8+T cell percentage than that in healthy control significantly (PO.05), and differences of T lymphocyte subsets expression between different states of SLE are not significant (P>0.05). (2) Expression of CD28 and CD 152 on T lymphocyte subsets: Compared with healthy control, expressions of CD28 and CD 152 on CD4+T cells and CD8+T cells in SLE are increasing strikingly (PO.05); in RA expressions of CD28 on T lymphocyte subsets is decreasing significantly (PO.05), on the contrary, expressions of CD 152 on them are increasing strikingly (PO.05). (3) Expression of ICOS on T lymphocyte subsets: Expression of ICOS on CD4+T cells and CD8+T cells in patients with SLE is significantly decreasing compared with patients with RA and healthy control (PO.05); that in patients with RA is similar to that in health control (P>0.05). In patients with different states of SLE— active or inactive non-lupus nephritis and lupus nephritis—expression of ICOS on CD4+T cells are all significantly less than that in healthy control (PO.05), and that on CD8+T cells all decrease nonsignificantly (P>0.05).
Differences of ICOS expression on T lymphocyte subsets between patients with different states of SLE are nonsignificant (P>0.05). (4) Expressions of CD 154 and CD30 on T lymphocyte subsets: Compared with healthy control, in patients with SLE expressions of CD 154 and CD30 on CD4+T cells or CD8+T cells both decrease, only the decease of CD154 and CD30 on CD4+T cells is significant (PO.05); however in patients with RA expressions of CD 154 and CD30 on T lymphocyte subsets are increasing or decreasing respectively, and only the comparison of expressions of CD154 and CD30 on CD4+T cells with healthy control is significant (PO.05), that on CD8+T cells is nonsignificant (P>0.05). In patients with inactive non-lupus nephritis, active non-lupus nephritis and lupus nephritis, expressions of CD 154 on CD4+T cells have the tendency of increasing but are all less than that in healthy control, compared with healthy control only that in inactive and active non-lupus nephritis are significant (PO.05), expressions of CD154 on CD8+T cells in different states of SLE are not significant (P>0.05). Differences of CD154 and CD30 on T lymphocyte subsets between different states of SLE are all not significant (P>0.05). (5) Expression of CD95 on T lymphocyte subsets: Expression of CD95 on CD4+T cells in patients with SLE and RA are more than that in healthy control (PO.05), and the difference between patients with SLE and RA is nonsignificant (P>0.05); expression of CD95 on CD8+T cells in patients with SLE and RA are both increasing, compared with healthy control, only that in RA has significance (PO.05). ? plasma level of cytokines IL-10 and IFN- y :The plasma levels of IL-10 and EFN- Y in patients with SLE have no significant difference with healthy control. In patients with different states of SLE—inactive non-lupus
nephritis, active non-lupus nephritis and lupus nephritis------the levels ofIL-10 increase gradually, and the mean value of IL-10 plasma levels in patients with lupus nephritis is more than that in healthy control (P>0.05); compared with healthy control, patients with different states of SLE have no significance (P>0.05). Differences between patients with different states of SLE are also not significant (P>0.05).Conclusions 1. Patients with SLE and RA have different characteristics of peripheral blood T lymphocyte subsets disturbances and are different in abnormal expressions of costimulators on T lymphocyte subsets, such as CD28^ CD152, ICOS> CD154^ CD30 and CD95. 2. Patients with SLE are characterized by T lymphocytes disturbance with increasing CD8+T cells, CD28 pathway plays an critical role in activating T lymphocytes, however, it is not the only way to activate T lymphocytes; inhibition of CD152 to CD28 pathway is abnormal and low expression of ICOS may be relative to inhibitory functions of CD152; CD154 and CD30 costimulators maybe don't play a critical role in the strengthened immune of SLE, and there are other costimulators to regulate immune responses; high expression of CD95 on CD4+T cells are maybe highly relative to the decreasing of CD4+T cells. 3. Patients with RA are characterized by the T lymphocytes disturbances with increasing CD4+T cells. The increasing of CD 152 on T lymphocyte subsets may be related with the decreasing of CD28 and CD8+T lymphocytes; the pathway of CD28 is not the only way and other costimulators are possibly more important to activate T lymphocytes in RA; the pathway of CD 154 may play an important role in excessive activation of T lymphocytes and B lymphocytes in RA; high expression of CD95 on CD8+T cells is
highly relative to the decrease of CD8+T cells. 4. With the deterioration of SLE, the disturbances of T lymphocytes are more obvious; the dynamic changes of expression of CD 154 on CD4+T cells and the plasma levels of FL-IO indicate that the effects of CD 154 and IL-10, as the important signal molecule and response molecules, are highly relative to costimulators' activation degree and the information power of costimulators.
方法 分析80例SLE患者(包括非狼疮性肾炎患者54例——其中非活动期患者24例、活动期患者30例,狼疮性肾炎患者26例),83例RA患者,40例健康志愿者外周血中T淋巴细胞免疫紊乱状态,采用流式细胞技术检测SLE、RA疾病组和健康对照组外周血或单个核细胞悬液中T淋巴细胞亚群表面共刺激分子CD28、CD152(CTLA-4)、ICOS(可诱导共刺激分子)、CD154(CD40L)、CD30分子和凋亡受体CD95(Fas)分子表达,酶联免疫吸附分析(ELISA)技术检测SLE患者组和健康对照组
Objective To analyse the expression of peripheral blood T lymphocyte subsets and costimulators on them CD28, ICOS, CD154 and CD30 which can activate and proliferate T cells and B cells, as well as CD152 (CTLA-4),CD95 which both play a negative role in T cells activation, proliferation——and plasma levels of cytokines EL-10 and IFN- γ in patients with Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA) to discuss the disturbance of T lymphocytes' and the costimulators' functions and pathways in human SLE and RA, further to lay the groundwork for finding better targets of biochemical therapy to patients with SLE and RA. Methods Analyse samples of 80 patients with SLE (54 patients with non-lupus nephritis, including 24 inactive and 30 active patients, and 26 patients with lupus nephritis), 83 patients with RA, and 40 healthy volunteers to learn the disturbances of peripheral blood T lymphocytes. Apply flow cytometry to determine the expressions of costimulators—CD28, CD152(CTLA-4), ICOS, CD154, CD30 and CD95 on T lymphocyte subsets—in patients with SLE or RA and healthy control, and emzyme-linked immunosorbent assay (ELISA)
to detect plasma levels of IL-10 and IFN- Y in patients with SLE and healthy control. All data are analysed by SPSS 11.0 statistics software and analysed by one-way ANOVA, Kruskal-Wallis Test or /-test, further comparing between groups by Dunnett T3 or Tamhane's T2 or Nemenyi Test. Results ? T lymphocyte subsets expression: Difference of CD3+T cell percentage between patients with SLE^ RA and healthy control is not significant (P>0.05). Compared with healthy control, in patients with SLE CD8+T cell percentage is increasing strikingly (PO.05); however, in RA CD4+T cell percentage and CD4/CD8ratio are both increasing significantly (PO.05). In different states of SLE, only patients with lupus nephritis have higher CD8+T cell percentage than that in healthy control significantly (PO.05), and differences of T lymphocyte subsets expression between different states of SLE are not significant (P>0.05). (2) Expression of CD28 and CD 152 on T lymphocyte subsets: Compared with healthy control, expressions of CD28 and CD 152 on CD4+T cells and CD8+T cells in SLE are increasing strikingly (PO.05); in RA expressions of CD28 on T lymphocyte subsets is decreasing significantly (PO.05), on the contrary, expressions of CD 152 on them are increasing strikingly (PO.05). (3) Expression of ICOS on T lymphocyte subsets: Expression of ICOS on CD4+T cells and CD8+T cells in patients with SLE is significantly decreasing compared with patients with RA and healthy control (PO.05); that in patients with RA is similar to that in health control (P>0.05). In patients with different states of SLE— active or inactive non-lupus nephritis and lupus nephritis—expression of ICOS on CD4+T cells are all significantly less than that in healthy control (PO.05), and that on CD8+T cells all decrease nonsignificantly (P>0.05).
Differences of ICOS expression on T lymphocyte subsets between patients with different states of SLE are nonsignificant (P>0.05). (4) Expressions of CD 154 and CD30 on T lymphocyte subsets: Compared with healthy control, in patients with SLE expressions of CD 154 and CD30 on CD4+T cells or CD8+T cells both decrease, only the decease of CD154 and CD30 on CD4+T cells is significant (PO.05); however in patients with RA expressions of CD 154 and CD30 on T lymphocyte subsets are increasing or decreasing respectively, and only the comparison of expressions of CD154 and CD30 on CD4+T cells with healthy control is significant (PO.05), that on CD8+T cells is nonsignificant (P>0.05). In patients with inactive non-lupus nephritis, active non-lupus nephritis and lupus nephritis, expressions of CD 154 on CD4+T cells have the tendency of increasing but are all less than that in healthy control, compared with healthy control only that in inactive and active non-lupus nephritis are significant (PO.05), expressions of CD154 on CD8+T cells in different states of SLE are not significant (P>0.05). Differences of CD154 and CD30 on T lymphocyte subsets between different states of SLE are all not significant (P>0.05). (5) Expression of CD95 on T lymphocyte subsets: Expression of CD95 on CD4+T cells in patients with SLE and RA are more than that in healthy control (PO.05), and the difference between patients with SLE and RA is nonsignificant (P>0.05); expression of CD95 on CD8+T cells in patients with SLE and RA are both increasing, compared with healthy control, only that in RA has significance (PO.05). ? plasma level of cytokines IL-10 and IFN- y :The plasma levels of IL-10 and EFN- Y in patients with SLE have no significant difference with healthy control. In patients with different states of SLE—inactive non-lupus
nephritis, active non-lupus nephritis and lupus nephritis------the levels ofIL-10 increase gradually, and the mean value of IL-10 plasma levels in patients with lupus nephritis is more than that in healthy control (P>0.05); compared with healthy control, patients with different states of SLE have no significance (P>0.05). Differences between patients with different states of SLE are also not significant (P>0.05).Conclusions 1. Patients with SLE and RA have different characteristics of peripheral blood T lymphocyte subsets disturbances and are different in abnormal expressions of costimulators on T lymphocyte subsets, such as CD28^ CD152, ICOS> CD154^ CD30 and CD95. 2. Patients with SLE are characterized by T lymphocytes disturbance with increasing CD8+T cells, CD28 pathway plays an critical role in activating T lymphocytes, however, it is not the only way to activate T lymphocytes; inhibition of CD152 to CD28 pathway is abnormal and low expression of ICOS may be relative to inhibitory functions of CD152; CD154 and CD30 costimulators maybe don't play a critical role in the strengthened immune of SLE, and there are other costimulators to regulate immune responses; high expression of CD95 on CD4+T cells are maybe highly relative to the decreasing of CD4+T cells. 3. Patients with RA are characterized by the T lymphocytes disturbances with increasing CD4+T cells. The increasing of CD 152 on T lymphocyte subsets may be related with the decreasing of CD28 and CD8+T lymphocytes; the pathway of CD28 is not the only way and other costimulators are possibly more important to activate T lymphocytes in RA; the pathway of CD 154 may play an important role in excessive activation of T lymphocytes and B lymphocytes in RA; high expression of CD95 on CD8+T cells is
highly relative to the decrease of CD8+T cells. 4. With the deterioration of SLE, the disturbances of T lymphocytes are more obvious; the dynamic changes of expression of CD 154 on CD4+T cells and the plasma levels of FL-IO indicate that the effects of CD 154 and IL-10, as the important signal molecule and response molecules, are highly relative to costimulators' activation degree and the information power of costimulators.
引文
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2. Akira Y, Alan DS, Mohamed HS. The Role of Novel T Cell Costimulatory Pathways in Autoimmunity and Transplantation. Journal of the American Society of Nephrology. 2002,13(2): 559-575.
3. Bohm I, Schild H. Apoptosis: the complex scenario for a silent cell death. Mol Imaging Biol. 2003,5(1): 2-14.
4. Iwai H, Abe M, Hirose S, et al. Involvement of inducible costimulator-B7 homologous protein costimulatory pathway in murine lupus nephritis. J Immunol. 2003, 171(6): 2848-2854.
5. Okamoto T, Saito S, Yamanaka H, et al. Expression and function of the co-stimulator H4/ICOS on activated T cells of patients with rheumatoid arthritis. J Rheumatol. 2003, 30(6): 1157-1163.
6. Nurieva RI, Treuting P, Duong J, et al. Inducible costimulator is essential for collagen-induced arthritis. J Clin Invest. 2003,111(5):701-706.
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